Synthesis method of valsartan

Abstract

The invention relates to a synthesis method of valsartan. The method comprises the following steps: by taking L-valine benzyl ester (I), para-bromobenzyl bromide (II) and benzonitrile (V) as primary raw materials, reacting the L-valine benzyl ester (I) with the para-bromobenzyl bromide (II) to produce a compound (III); performing acrylation reaction on the compound (III) and ammonium valeryl chloride to obtain (S) 2-[(4-bromobenzyl)-valeryl]-3-methyl benzyl butyrate (IV); after performing n-butyllithium treatment on the benzonitrile (V), reacting with trimethyl borate to obtain 2-cyanophenyl boric acid (VI); performing Suzuki coupling reaction on the compound (IV) and the compound (VI) to obtain (S)-N-valeryl-N-[(2'-cyanobiphenyl-4-yl)methyl]-valine benzyl ester (VII); reacting the compound (VII) with azidotributyltin to obtain (S)-N-valeryl-N-[[2'-(N'-tributyltin-5-tetrazolyl)-4-diphenyl]methyl]-valine benzyl ester (VIII); performing protecting group removal reaction and hydrolysis reaction on the compound (VIII) to obtain target product valsartan (X). The synthesis method has the advantages of mild synthesis condition, high yield, less using amount of solvent and low production cost and is suitable for industrial production.

Description

technical field [0001] The invention relates to a method for preparing a compound, in particular to a method for synthesizing valsartan. Background technique [0002] Valsartan is an orally effective and specific angiotensin II (AT1) receptor antagonist that selectively acts on AT1 receptor subtypes, blocking the binding of Ang II to AT1 receptors (its specificity The effect of antagonizing the AT1 receptor is about 20,000 times greater than that of the AT2 receptor), thereby inhibiting vasoconstriction and the release of aldosterone, resulting in a hypotensive effect. Its chemical name is (S)-N-n-pentanoyl-N-[[2'-(1H-5-tetrazolyl)-4-diphenyl]methyl]-valine, and its chemical structure is shown in X . [0003] The known valsartan synthesis methods related to the present invention have the following patents: US5399578, CN1317485, WO04 / 026847, WO05 / 049586, US0281801, CN101223149. [0004] US5399578 first reported the synthesis method of valsartan. This route is based on 2'-c...

AI Technical Summary

Problems solved by technology

But in the process of synthesizing N-n-pentanoyl-N-(2'-cyanobiphenyl-4-methylene)-valine methyl ester, use the toluene of high boiling point as solvent, need at higher Reaction at high temperature leads to lower yield and more troublesome purification process; diisopropylethylamine is used in the process of synthesizing valsartan methyl ester, which will lead to the formation of by-products

[0009] CN101223149 discloses a new method for the synthesis of valsartan, using Suzuki coupling reaction to synthesize trityl valsartan, but due to the relatively large steric hindrance of the tetrazole group and the trityl group, C-C in the reaction The actual yield of the coupling is low, affecting the yield of the final product

Images